USPTO Patents Application 09993647

WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau

PCT

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification 5
A61K 31/00, 31/475, 31/40

A2

(11) International Publication Number: WO 94/25012

(43) International Publication Date: 10 November 1994 (10.11.94)

(21) International Application Number: PCT/EP94/01240

(22) International Filing Date: 20 April 1994 (20.04.94)

(30) Priority Data:

9308802.9

28 April 1993 (28.04.93)

GB

(71) Applicant (for all designated States except US): SMTTHKLINE

BEECHAM PLC [GB/GB]; New Horizons Court, Brentford,
Middlesex TW8 9EP (GB).

(72) Inventors; and

(75) Inventors/Applicants (for US only): BLACKBURN, Thomas,
Paul [GB/GB]; SmithKline Beecham Pharmaceuticals, Cold-
harbour Road, The Pinnacles, Harlow, Essex CM19 5 AD
(GB). KENNETT, Guy, Anthony [GB/GB]; SmithKline
Beecham Pharmaceuticals, Coldharbour Road, The Pinna-
cles, Harlow, Essex CM19 5 AD (GB). BAXTER, Gor-
don, Smith [GB/GB]; SmithKline Beecham Pharmaceu-
ticals, Coldharbour Road, The Pinnacles, Harlow, Essex
CM19 5 AD (GB).

(74) Agent: GIDDINGS, Peter, J.; Corporate Intellectual Property,
SmithKline Beecham, Mundells, Welwyn Garden City,
Hertfordshire AL7 1EY (GB).

(81) Designated States: AT, AU, BB, BG, BR, BY, CA, CH, CN,
CZ, DE, DK, ES, FI, GB, GE, HU, JP, KG, KP, KR,
KZ, LK, LU, LV, MD, MG, MN, MW, NL, NO, NZ, PL,
PT, RO, RU, SD, SE, SI, SK, TJ, TT, UA, US, UZ, VN,
European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR,
IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).

Published

Without international search report and to be republished
upon receipt of that report.

(54) Title: MEDICAMENTS FOR TREATMENT OF MIGRAINE, EPILEPSY AND FEEDING DISORDERS
(57) Abstract

A novel method of medical treatment, in particular the treatment and prevention of epilepsy and migraine.

FOR THE PURPOSES OF INFORMATION ONLY

Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
applications under the PCT.

AT

Austria

GB

United Kingdom

MR

Mauritania

XV

Australia

GE

Georgia

MW

Malawi

BB

Barbados

GN

Guinea

NE

Niger

BE

Belgium

GR

Greece

NL

Netherlands

BF

Burkina Faso

HU

Hungary

NO

Norway

BG

Bulgaria

IE

Ireland

NZ

New Zealand

BJ

Benin

IT

Italy

PL

Poland

BR

Brazil

JP

Japan

PT

Portugal

BY

Belarus

KE

Kenya

RO

Romania

CA

Canada

KG

Kyrgystan

RU

Russian Federation

CF

Central African Republic

KP

Democratic People's Republic

SD

Sudan

CG

Congo

of Korea

SE

Sweden

ce

Switzerland

KR

Republic of Korea

SI

Slovenia

CI

C6te d'lvoire

KZ

Kazakhstan

SK

Slovakia

CM

Cameroon

U

Liechtenstein

SN

Senegal

CN

China

LK

Sri Lanka

TD

Chad

CS

Czechoslovakia

LU

Luxembourg

TG

Togo

CZ

Czech Republic

LV

Latvia

TJ

Tajikistan

DE

Germany

MC

Monaco

TT

Trinidad and Tobago

DK

Denmark

MD

Republic of Moldova

UA

Ukraine

ES

Spain

MG

Madagascar

US

United States of America

FI

Finland

ML

Mali

UZ

Uzbekistan

FR

France

MN

Mongolia

VN

Viet Nam

GA

Gabon

WO 94/25012 PCT/EP94/01240

MEDICAMENTS FOR TREATMENT OF MIGRAINE, EPILEPSY AND
FEEDING DISORDERS

The present invention relates to a novel method of medical treatment, in particular
the treatment and prevention of epilepsy and migraine.
5 Compounds which have activity as 5HT2C receptor antagonists and activity at the

rat fundus serotonin receptor are known in the art. Examples of such compounds are
disclosed in WO 93/18028 and WO 92/05170.

Rat fundus serotonin receptors are presently known as 5HT2B receptors. It has
now been found that these 5HT2B receptors are located in regions of the brain, for
10 example in the hippocampus, habenula and hypothalamus regions. It is expected, as a
consequence, that compounds which exhibit 5HT2B receptor modulating activity will be
of use in the treatment of certain CNS disorders, in particular epilepsy, migraine and
feeding disorders. It has also been found that these 5HT2B receptors are located in the
gastrointestinal tract. Compounds which exhibit 5HT2B receptor modulating activity are
15 therefore also expected to be of use in the treatment of GI disorders such as irritable bowel
syndrome (TBS).

The present invention therefore provides, in a first aspect, the use of a 5HT2B
receptor modulator in the treatment of epilepsy, migraine and feeding disorders. It will be
appreciated by those skilled in the art that the term '5HT2B receptor modulator' refers to a
20 compound which acts as an agonist or antagonist at the 5HT2B receptor.

In particular, for the treatment or prophylaxis of epilepsy and feeding disorders
such as anorexia nervosa, the 5HT2B receptor modulator should preferably be a 5HT2B
receptor agonist. Preferred 5HT2B receptor agonists include compounds of formula (I)
and pharmacuetically acceptable salts thereof:

25

3 4 5 6

I 2

R

a)

30 in which

Rl is an optionally substituted phenyl, thienyl or furyl ring;
R2 is hydrogen or Ci_6 alkyl;

R3 and R 4 are independently hydrogen or C\.^ alkyl;
R5 and R^ are independendy hydrogen or C\.^ alkyl;

- 1 -

WO 94/25012

PCT/EP94/01240

X is O, S or NH; and

n and m are independently 1 or 2.

A particularly preferred 5HT2B receptor agonist of formula (I) is l-(5-(2-
tWenylmethoxy)-lH-indol-3yl-)propan-2-amine.
5 For the treatment or prophylaxis of migraine and IBS the 5HT2B receptor

modulator should preferably be a 5HT2B receptor antagonist.

Preferred 5HT2B receptor antagonist compounds expected to be useful in the
above treatments include those of formula (IA) or pharmaceutically acceptable salts
thereof:

(IA)

wherein:

15 P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic

heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or
sulphur,

Rj is hydrogen or Ci_6 alkyl;

R2, R3, Rio ana * Ri 1 are independendy hydrogen or Ci_g alkyl, or R\q and Ri 1 together
20 form a bond, or R2 and Rio or R3 and Ri 1 together form a C2-6 alkylene chain;

R4 is hydrogen, Ci_6 alkyl, halogen, NRgRt), OR12 or COOR12, where Rg, R9 and R12

are independently hydrogen or C 1.5 alkyl;

R5 and Rg are independendy hydrogen or Ci_6 alkyl; and

R7 is hydrogen, Ci_6 alkyl, C\.^ alkoxy or halogen; and wherein the urea moiety is
25 attached at the 4-, 5- or 6-position of the indole or indoline ring.

Preferred compounds of formula (IA) include those exemplified in WO 93/18028

and WO 92/05170, in particular N-(l-Memyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl) urea.

Compounds of formula (IA) can be prepared according to the procedures outlined in WO

93/18028 and WO 92/05170.
30 Further preferred 5HT2B receptor antagonist compounds include those of formula

(IB) or pharmaceutically acceptable salts thereof:

WO 94/25012

PCT/EP94/01240

R (CR R ) n

II

o

7 I 1

wherein:

P represents a quinoline or isoquinoline residue, or a 5- or 6-membered aromatic
heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or
5 sulphur;

is hydrogen or Cj_6 alkyl;
R 2 , r3^ rIO and r1 1 are independendy hydrogen or Cj.g alkyl, or RlO and together

form a bond, or R 2 and R^ or R^ and R* * together form a C2-6 alkylene chain;
R 4 is hydrogen, Ci.g alkyl, halogen, NR 8 R 9 or OR 12 where R 8 , R 9 and R 12 are
1 0 independently hydrogen or C j _6 alkyl;

R^ is hydrogen or Cj.g alkyl;

R^ is hydrogen, Cj_6 alkyl, OR* 2 or halogen, where R* 2 is hydrogen or Cj.6 alkyl; and
n is 2 or 3; and

the groups R*3 and R^ 4 are independendy hydrogen or Cj_6 alkyl.
15 Preferred compounds of formula (IB) include:

5- memyl-l-(3-pyridylcarbamoyl)-2,3Hlmydropyrrolo[2,3-f]-indole,

6- memyl-3-(5^uinolmylcarbamoyl)-2,3-dihydro-pyirolo[3^-e]indole and
N-(5-isoquinolyl)-5-methyl-2,3-dihydropyrrolo[2,3-f] indole- 1-carboxamide and
pharmaceurically acceptable salts thereof.

20 Compounds of formula (IB) can be prepared according to the procedure outlined in

PCTEP93/02031.

Certain compounds of formula (I), (IA) and (IB) are capable of existing in
stereoisomer^ forms. It will be understood that the invention encompasses all geometric
and optical isomers of these compounds and the mixtures thereof including racemates.
25 Tautomers of compounds of formula (I), (IA) and (IB) and mixtures thereof will also
exhibit 5HT2B activity and therefore also form an aspect of the invention.

The compounds of the formula (I), (IA) and (IB) can form acid addition salts with
acids, such as conventional pharmaceutically acceptable acids, for example maleic,
hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic,
30 tartaric and methanesulphonic.

The present invention further provides a method of treatment or prophylaxis of
CNS disorders such as epilepsy, migraine and feeding disorders, and GI disorders such as

WO 94/25012

PCT/EP94/01240

IBS, which comprises administering to a host in need thereof an effective amount of a
5HT2B receptor modulator or a pharmaceutically acceptable salt thereof.

In a still further aspect, the invention provides the use of a 5HT2B receptor
modulator or a pharmaceutically acceptable salt thereof in the manufacture of a
5 medicament for the treatment or prophylaxis of CNS disorders such as epilepsy, migraine
and feeding disorders and GI disorders such as IBS.

Compounds which exhibit 5HT2B receptor agonist and antagonist activity are also
expected to be of use in the treatment and prophylaxis of other CNS disorders. Such
disorders include anxiety, depression, obsessive compulsive disorders, pain, memory
10 disorders such as Alzheimer's disease, sleep disorders, panic attacks, withdrawal from drug
abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia and also
disorders associated with spinal trauma and/or head injury such as hydrocephalus.

When used in therapy, the 5HT2B receptor agonists and antagonists are usually
formulated in a standard pharmaceutical composition. Such compositions can be
15 prepared using standard procedures.

A pharmaceutical composition of the invention, which may be prepared by
admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted
for oral, parenteral or rectal administration and, as such, may be in the form of tablets,
capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders,
20 injectable or infusible solutions or suspensions or suppositories. Orally administrable
compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may
contain conventional excipients, such as binding agents, fillers, tabletting lubricants,
disintegrants and acceptable wetting agents. The tablets may be coated according to
25 methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily
suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product
for reconstitution with water or other suitable vehicle before use. Such liquid preparations
may contain conventional additives such as suspending agents, emulsifying agents,
30 non-aqueous vehicles (which may include edible oils), preservatives, and, if desired,
conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are prepared utilising a
compound of the invention or pharmaceutically acceptable salt thereof and a sterile
vehicle. The compound, depending on the vehicle and concentration used, can be either
35 suspended or dissolved in the vehicle. In preparing solutions, the compound can be

dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and
sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and

WO 94/25012

PCT/EP94/01240

buffering agents are dissolved in the vehicle. To enhance the stability, the composition
can be frozen after filling into the vial and the water removed under vacuum. Parenteral
suspensions are prepared in substantially the same manner, except that the compound is
suspended in the vehicle instead of being dissolved, and sterilisation cannot be
5 accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide
before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is
included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to
60% by weight, of the active material, depending on the method of administration.

10 The dose of the compound used in the treatment of the aforementioned disorders

will vary in the usual way with the seriousness of the disorders, the weight of the sufferer,
and other similar factors. However, as a general guide suitable unit doses may be 0.05 to
1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses
may be administered more than once a day, for example two or three a day, so that the

15 total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend
for a number of weeks or months.

-5-

WO 94/25012

PCT/EP94/01240

Examples

l-(5-(2-thienylmethoxy)-lH-indol-3yI-)propan-2-amine

5 Description 1

5-Benzyloxy-3-(2-trifluoroacetylamino)propyIindole (Dl)

Trifluoroacetic anhydride (2.4 ml, 17 mmol) was added to a solution of 3-(2-
aminopropyl)-5-benzyloxyindole (prepared by the method of A.S J 7 . Ash and W.R.

10 Wragg, J. Chem. Soc, 1958, 3887; 4.65g, 16.6 mmol) and 4-(N,NHiimemylamino)
pyridine (2.07g, 17 mmol) in dry dichloromethane (40 ml) at 0° C. The mixture was
stirred for lh at 0° C, then washed twice with water, dried and evaporated. The residue
was chromatographed on silica gel eluted with 1-2% methanol/dichloromethane. Eluted
product was recrystallised from dichloromethane/petrol to give the title compound (3.7 lg,

15 59%).

NMR (CDC1 3 ) 8 : 1.23 (3H, d, J = 7), 2.46 (2H, m), 4.38 (1H, m), 5.11 (2H, s), 6.23
(1H, d, J = 7), 6.97 (2H, m), 7.13 (1H, d, J = 2), 7.30 (1H, d, J = 7), 7.38 (3H, m), 7.49
(2H, m), 8.03 (1H, s).
20 MS (EI) m/e 376 (M + )

Description 2

5-Hydroxy-3-(2-trifluoroacetylamino)propyIindole (D2)

25 Benzyloxyindole (Dl, 3.7g, 9.8 mmol) was shaken with 5% palladium on charcoal (0.47g)
in ethanol (50 ml) under hydrogen at 50 p.s.i., for 43h. The mixture was filtered through
kieselguhr and the filtrate was evaporated. The residue was chromatographed on silica gel
eluted with 2% methanol/dichloromethane. Eluted product was recrystallised from
dichloromethane/methanol to give the title compound (2.22g, 79%)

30

NMR (CDCI3/CD3OD) 8 : 1.22 (3H, d, J = 7), 2.83 (1H, dd, J = 14,7), 3.00 (1H, dd,
J = 14,5), 4.34 (1H, m), 6.82 (1H, dd, J = 7,2), 6.99 (1H, s), 7.08 (1H, d, J = 2), 7.22
(1H, d, J = 7), 8.28 (1H, s).

-6-

WO 94/25012

PCT/EP94/01240

Description 3

5-(2-thienyImethoxy)-3-(2-trifluoroacetyIamino)indole (D3)

A solution of hydroxyindole (D2, 2.22g, 7.76 mmol) in dry dimethylformamide (15 ml)
5 was added to a suspension of sodium hydride (80% in oil, 0.28g, 9.3 mmol) in
dimethylformamide (15 ml) at 0° C. After 10 min at 0° C a solution of 2-
chloromethylthiophene (1.06g, 8 mmol) in dimethylformamide (10 ml) was added and the
mixture was heated for 2h at 90-1 10° C. The mixture was then evaporated and the residue
was dissolved in dichloromethane and washed with dilute hydrochloride acid (pH3),
10 sodium bicarbonate and water. The organic phase was dried and evaporated, and the

residue was chromatographed on silica gel with 1-2% methanol/dichloromethane, to give
the tide compound (1.87g, 63%).

NMR (CDC1 3 ) 8 : 1.26 (3H, d, J = 7), 2.98 (2H, m), 4.38 (1H, m), 5.28 (2H, s), 6.22 (1H,
15 d, J = 7), 6.95 (1H, dd, J = 7,2), 7.00 (2H, m), 7.13 (1H, d, J = 4), 7.18 (1H, d, J = 2), 7.29
(1H, d, J = 7), 7.34 (1H, d, J = 6), 8.05 (1H, s).

MS (EI) m/e 382 (M+)

20 Example 1

l-[5-(2-Thienylmethoxy)-lH-indol-3-yl]propan-2-amine hydrochloride (El)

The trifluoroacetyl compound (D3, 1.86g, 4.87 mmol) was heated under reflux with
potassium carbonate (3.82g, 27.7 mmol) in methanol (90 ml) and water (6 ml) for 6.5h.

25 The mixture was partially evaporated and then partitioned between dichloromethane and
water. The aqueous phase was further extracted with dichloromethane. Combined organic
phases were washed with brine, dried and evaporated. The crude product (1.39g) was
dissolved in ethyl acetate (50 ml) at 0° C and 1M hydrogen chloride/ether (4.9ml, 4.9
mmol) was added slowly. After stirring for 5 min at 0° C, the precipitate was filtered off,

30 washed with ethyl acetate and dried, to give the tide compound (1.40g, 89%), m.p. 203-
205° C.

NMR (d6-DMSO) 5 : 1.19 (3H, d, J = 7), 2.80 (1H, dd, J = 14, 7), 3.09 (1H, dd, J = 14,
5), 5.31 (2H, s), 6.80 (1H, dd, J = 7,2), 7.03 (1H, dd, J = 6, 4), 7.20-7.31 (4H, m), 7.54
35 (1H, d, J = 6), 8.01 (1H, s).
MS (CI) m/e 287 (MH+)

WO 94/25012

PCT/EP94/01240

Pharmacological Data
Epilepsy

5

5HT2B receptor agonists are expected to be of use in the treatment of epilepsy since
l-(5-(2-tWenylmemoxy)-lH-mdol-3yl-)propan-2-amine (1-100 mgkg -1 s.c. 30 min
pretest) significantly raised the current at which 50% of mice convulsed in the mouse
maximal electroshock seizure (MES) threshold test, carried out as described in Loscher
10 and Schmidt, (1988, Epilepsy Res., 2, 145-181). This is consistent with the presence of
5HT2B receptor mRNA in the rat hippocampus, an area which can mediate convulsions
(McNamara et al., 1993, in Epilepsy, models, mechanisms and concepts, Ed,
Schwartzkroin, Cambridge University Press, pp 27-47).

15 IBS

5HT2B receptors are expressed in the stomach fundus of the rat (Foguet et al., 1992,
EMBO J. , 1 1, 3481-3487) where they mediate a contractile response to
5-hydroxytryptamine (5-HT). l-(5-(2-tMenylmemoxy)-lH-mdol-3yl-)propan-2-amine
20 also causes contraction of rat stomach fundus and is a selective agonist at 5HT2B receptors
in this preparation (pEC50[95% Confidence limits] = 8.47 [8.04 - 8.90]).

In bilaterally vagotomised spinal rats, l-(5-(2-thienylmethoxy)-lH-indol-3yl-)propan-2-
amine (1-100 ugkg"* i v.) evokes a dose-dependant and significant increase in gastric

25 motility in vivo causing a significant increase in intragastric pressure (for methodology see
Dhasmana et al., 1992, Eur. J. Pharmacol., 213, 293 299). This action is blocked by
selective 5HT2B receptor antagonists such as those disclosed in Patent (WO 93/18028)
and supports a use for 5HT2B receptor modulators in disorders of gastric motility. Such a
use is further supported by the observation that the 5HT2B receptor antagonist 6-methyl-

30 3-(5-qumomiylcarbamoyl)-2,3-dihydro-pyrrolo[3,2-e]indole (10 - 10000 pgkg -1 s.c.)

significantly reduced 5-hydroxytryptophan-induced increase in faecal pellet output in the
conscious mouse (for methods see Banneret al., 1993, Br. J. Pharmacol., 110, 17P).

Feeding Disorders

35

When given at doses between 1 and 100 mgkg -1 s.c. 30 min pretest, or at doses between 1
and 30ug Lev. 4 min pretest, l-(5-(2-tmenylmemoxy)-lH-mdol-3yl-)propan-2-amine

WO 94/25012

PCT/EP94/01240

significantly increases feeding behaviour and food intake in freely-feeding, sated rats. The
methodology used in these studies was as described in Kennett et al., (1992, Eur. J.
Pharmacol., 141, 429-435). Thus 5HT2B receptor agonists are expected to be of
therapeutic use in the treatment of feeding disorders such as anorexia nervosa and bulimia.
5 Furthermore, selective 5HT2B receptor antagonists are likely to have appetite suppressant
actions and be beneficial in the treatment of obesity. These claims are supported by the
presence of high levels of 5HT2B receptor mRNA in the hypothalamus (studies carried
out at SmithKline Beecham Pharmaceuticals), an area long associated with the control of
appetite (Sugrue et al., 1987, Neuropharmacology, 32, 145-182).

10

Migraine

l-(5-(2-tMenylmemoxy)-lH-mdol-3yl0propan-2-amine (mean pEC50 [95% C.L] 7.9 [7.7

- 8.1] with an intrinsic activity (IA)of 0.84 + 0.04, n=9) and 5-HT (mean pEC50 [95%
15 C.L] 8.2 [8.0 - 8.3] IA 1.0,n=9) evokes endothelium-dependant relaxation of isolated rat

jugular vein via activation of 5HT2B receptors with a maximal relaxation to 5HT of 73.8
+ 4.6%, n=9 (for basic methods see Bodelsson et al., 1993, J. Pharm. Exp. Ther, 264, 709

- 716). Endothelium-dependant 5HT-induced relaxation of isolated smooth muscle
preparations has been suggested to be due to release of endothelium derived nitric oxide

20 (Martin et al., 1992, Br. J. Pharmacol, 105, 643 - 652). Local application of 5HT to

cerebral arterioles in vivo induces dilatation which is antagonised by inhibitors of nitric
oxide synthase (Parsons et al., 1992, In; 5-Hydroxytryptamine mechanisms in primary
headaches, Ed. Olesen & Saxena, Raven Press, NY, ppl57 - 162) suggesting the presence
of cerebrovascular 5HT2B receptors. Furthermore the pharmacological character of the

25 receptor mediating the dilation is that expected for 5HT2B- Agonist potency order a-

methyl 5HT = 5HT > 5CT. (Pryke et al., Brit. J. Pharmacol. 1989, 98, 685p). Dilatation
of cerebral arteries has been shown to induce a migraine-like headache (Nichols et al.,
1991, Stroke, 21, 555 - 559). 5HT2B receptor modulators are therefore expected to be
effective in the treatment or prophylaxis of migraine.

-9-

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CLAIMS:

1. Use of a 5HT2B receptor antagonist for the treatment of migraine.

2. Use according to claim 1 in which the 5HT2B receptor antagonist is a
5 compound of formula (IA) or a pharmaceutically acceptable salt thereof:

10

15

20

25

(IA)

wherein:

P represents a quinoline or isoquinoline residue or a 5- or 6-membered aromatic
heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or
sulphur,

Rl is hydrogen or Cj_6 alkyl;

R2, R3, Rio and Rj j are independently hydrogen or Ci_6 alkyl, or Rjq and Ri j together

form a bond, or R2 and Rjq or R3 and R\ j together form a C2-6 alkylene chain;

R4 is hydrogen, Ci.g alkyl, halogen, NRgR<j, OR12 or COOR12, where Rg, R9 and R12

are independently hydrogen or Cj.g alkyl;

R5 and R6 are independendy hydrogen or Cj_6 alkyl; and

R7 is hydrogen, Ci_g alkyl, C\.^ alkoxy or halogen; and wherein the urea moiety is
attached at the 4-, 5- or 6-position of the indole or indoline ring.

3. Use according to claim 1 in which the 5HT2B receptor antagonist is a
compound of formula (IB) or a pharmaceutically acceptable salt thereof:

13 14
(CR R ) n

(IB)

wherein:

P represents a quinoline or isoquinoline residue, or a 5- or 6-membered aromatic

- 10-

WO 94/25012

PCT/EP94/01240

heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or
sulphur,

R.1 is hydrogen or Ci.g alkyl;

R 2 , r3, rIO and Rl 1 are independently hydrogen or Cj.^ alkyl, or and R* * together
5 form a bond, or R 2 and R*0 or R3 and R* 1 together form a C2-6 alkylene chain;

R 4 is hydrogen, C\_6 alkyl, halogen, NR 8 R 9 or OR 12 where R 8 , R 9 and R 12 are

independently hydrogen or Cj.g alkyl;
R5 is hydrogen or Ci_6 alkyl;

R7 is hydrogen, C\.^ alkyl, OR* 2 or halogen, where R* 2 is hydrogen or Cj_6 alkyl; and
10 n is 2 or 3; and

the groups R*3 and R* 4 are independendy hydrogen or Cj.6 alkyl.

4. Use according to claim 3 in which the compound of formula (IB) is

5- methyl- 1 -(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f]indole,

6- memyl-3-(5-qumolmylcarbamoyl)-2,3Kiihydro-pyrrolo[3,2-e]indole, or
15 N-(5-isoquinolyl)-5-methyl-2,3-dihydropyrrolo[2,3-f] indole- 1-carboxamide

or pharmaceutically acceptable salts thereof.

5. Use of a 5HT2B receptor agonist in the treatment of epilepsy and feeding
disorders.

6. Use according to claim 5 in which the 5HT2B receptor agonist is a
20 compound of formula (I) and pharmacuetically acceptable salts thereof:

3 4 5 6

I 2

R

a)

25 in which

Rl is an optionally substituted phenyl, thienyl or furyl ring;

R 2 is hydrogen or Ci_6 alkyl;

R3 and R 4 are independently hydrogen or Ci_6 alkyl;

R^ and R*> are independendy hydrogen or C j.g alkyl;
30 X is O, S or NH; and

n and m are independendy 1 or 2.

7. Use according to claim 6 in which the 5HT2B receptor agonist is l-(5-(2-

tMenylmemoxy)-lH-mdol-3yl-)propan-2-amine or a pharmacuetically acceptable salt

thereof.

- 11 -